Our work focuses on T regulatory (Treg) cells, which inhibit both self and allogeneic immune responses making these cells attractive for novel cell-based therapy approaches to promote tolerance and control autoimmune diseases, including type 1 diabetes. However, the use of these cells for therapy is hindered by the inability to generate the sufficient number of cells required to inhibit the desired immune response(s) and achieve stable engraftment of the donor Treg cell inoculums. Furthermore, the constant production of Treg cells from the thymus creates a continuous, competitive barrier that our laboratory has demonstrated must be overcome in order to successfully use Treg cells for therapy. Previous studies from our laboratory demonstrate that the single adoptive transfer of Treg cells into neonatal IL-2R?-/- mice, which have impaired IL-2 signaling and Treg cell function, fully prevents severe autoimmunity that would otherwise be lethal for these mice in a matter of a few weeks. Therapy with wild-type Treg cells allows these mice to remain autoimmune-free and to have a normal life span, and is accompanied by life-long donor Treg cell engraftment. Importantly, we show that allo-Treg cells also engraft which confers tolerance to skin allografts and restores self-tolerance. These findings show that under the right biological conditions adoptive transfer of even a small, unmanipulated number of Treg cells is very effective at achieving tolerance and results in long-term engraftment. This IL-2R?-/- model offers some clues to the mechanisms that may be required for successful therapy. The overall goals of this proposal are: 1) to elucidate the mechanisms that regulate successful Treg therapy and 2) to develop clinically translatable protocols for the treatment of T1D, using preclinical models to investigate if clinically applicable Treg therapy can be achieved for the prevention or reversal of autoimmune diabetes or to suppress graft rejection of islet cell transplantation for the treatment of diabetes. The present research proposal is designed to test the hypothesis that stable donor Treg engraftment requires immunomodulation and that there is in vivo biological selection by antigen for therapeutic Tregs leading to successful immunotherapy. Based on this hypothesis, the specific aims of this proposal are: 1) to identify mechanisms that promote stable donor Treg engraftment in NOD mice through immunomodulation with clinically translatable combinatorial regimens. and 2) to determine whether selection and expansion of antigen (Ag)-specific donor Tregs occurs following aCD3 and Treg infusion. This research will generate novel data that are required for the design of successful therapies based on Treg cells. Further, the demonstration of therapeutic synergy with agents that have been or are being used in clinical trials for new onset diabetes will provide impetus and needed pre-clinical data for the design of future clinical trials that combine adoptive Treg transfer with immunomodulation, and perhaps antigen-specific therapies.

Public Health Relevance

The immune system focuses on attacking and destroying foreign materials and avoids attacking self-tissues. But this process can fail leading the immune system to attack self-tissues leading to autoimmune diseases and in the context of type 1 diabetes (T1D) the insulin-producing ? cells are destroyed. Pancreatic and islet transplantation are recognized as approved and experimental treatments, respectively, for T1D, but therapeutic success is curtailed by chronic rejection and recurrence of autoimmunity. A significant complication of such transplantation is that life-long immune suppression is required which is toxic, not always successful, and impairs normal immune response to infectious microorganisms. One mechanism that immune system employs to keep these self-reacting cells in check is through a population of regulatory T cells that function by blocking the destruction of self-tissues. These regulatory T cells can also block immune responses to transplanted tissues, thereby preventing their destruction. These proposed studies will contribute to the potential therapeutic use of Treg cells for successful treatment of T1D patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI101278-01A1
Application #
8707637
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Bourcier, Katarzyna
Project Start
2013-08-15
Project End
2014-07-31
Budget Start
2013-08-15
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$360,725
Indirect Cost
$125,725
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Pugliese, Alberto (2014) Advances in the etiology and mechanisms of type 1 diabetes. Discov Med 18:141-50